PROJECT SUMMARY/ABSTRACT The three-dimensional (3D) conformation of the genome plays an integral role in regulating gene expression. The genome folds into megabase-long topologically associating domains (TADs), regions that self-interact, but rarely contact regions outside the domain. TADs modulate gene regulation by restricting interactions of regulatory elements, like enhancers, to their target genes. Disruption of the insulating boundaries between TADs by large-scale rare variants can cause severe developmental phenotypes. However, the relationship between the genetic basis underlying common phenotypes and 3D genome architecture across different cell-types is not understood. Common small-scale (e.g. SNP) variation may change 3D genome structure in a cell-type-specific manner, leading to changes in gene expression and disease risk. As genome-wide association studies (GWAS) become more common, cell-type-specific interpretation of disease-associated variants is essential for mechanistic understanding of disease. This work will examine variation in different 3D contexts across diverse cell-types, quantifying their evolutionary constraint and contribution to common phenotypes. I hypothesize that genetic variation at TAD boundaries contributes more to the burden of common disease than variation in TADs. Furthermore, I hypothesize that disruption of cell-type-specific TAD boundaries contributes to diseases in relevant cell-types. First, 37 cross-cell-type and four cross-species 3D genome maps will be integrated to measure 3D element functional conservation. Comparing different 3D contexts (i.e. TADs and boundaries) across cell-types and species will provide a framework for integrating 3D genome maps into interpretation of disease-associated variants. Second, the relationship between 3D architecture and the genetic architecture of 28 common complex traits will be mapped through partitioned heritability analysis. This will reveal if TAD boundaries have a greater genetic contribution to different common diseases than TADs. Third, cell-type-specific 3D elements will be assessed for cell-type-specific functional effects through enrichment analyses of existing functional annotations and biobank data. This work will enable cell-type-specific and 3D structural-aware variant interpretation by quantifying the relationship between the genetic architecture of disease and 3D genome structure. Furthermore, this project, when combined with rigorous clinical and scientific training, will provide opportunity for interdisciplinary collaboration with experts and mastery of multiple techniques in human genetics, well-equipping me to become a physician-scientist leader in genetics.